In cancer radiotherapy, 2-nitroimidazole derivatives are known to be useful drugs as radiation-sensitizers for increasing radiation sensitivity of hypoxic cancer cells with radioresistance.
Among these 2-nitroimidazole derivatives, 1-(1-hydroxymethyl-2,3-dihydroxypropyl)oxymethyl-2-nitroimidazole, which is represented by the following formula (1):
(hereinafter may be referred to as compound (1)), has particularly high hydrophilicity and virtually no transferability to neurocytes, to thereby serve as a radiation sensitizer having no toxicity to the central nervous system (see Patent Documents 2 and 3).
In addition to exhibiting radiation sensitizing effect on hypoxic cells, these compounds (1) have hydroxyl-group-removing action in nucleic acid (see Patent Document 4), apoptosis-signal maintaining action (see Patent Document 5), etc. Thus, the compounds (1) are considered to be useful drugs in cancer therapy.
Compound (1) has two asymmetric carbon atoms, and four stereoisomers: RR form, SS form, SR form, and RS form. Among these isomers, at present, clinical application is studied on only a racemic mixture of SR form and RS form.
All species of compound (1) have characteristics including high crystallinity, both water-solubility and lipid-solubility, and high tumor-affinity. These characteristics are thought to be attributed to an acyclic sugar nucleoside-like structure.
However, since compound (1) has high crystallinity and amphipathic nature, the crystal structure thereof must be broken in order to dissolve it in an aqueous carrier. This process requires heating and shaking for a long period of time. Therefore, long-term preparation must be performed before radiation, which problematically impairs operability. Such operation may affect the stability of the produced drug formulation.
Furthermore, the stability of a solution of compound (1) in aqueous carrier is readily lost at room temperature or higher. Thus, the solution must be stored at low temperature (e.g., 5° C.), and storage at low temperature makes dissolution of compound (1) more difficult, which is also problematic.
In addition, when a lyophilized formulation of compound (1) is employed, a small amount of water considerably affects the stability of the drug formulation.
Meanwhile, creatinine is known to be an optional ingredient of a pharmaceutical composition. For example, a compound which is less soluble in water forms a solid solution with creatinine, to thereby convert the crystal form to an amorphous form, whereby dispersion and dissolution of the compound in water are promoted (Patent Document 6). However, creatinine has never been known to exhibit a direct effect on solubility of a compound.    Patent Document 1: JP-A-1991-223258    Patent Document 2: WO 1994/014778    Patent Document 3: JP-A-2003-321459    Patent Document 4: JP-A-2005-27515    Patent Document 5: JP-A-1997-77667    Patent Document 6: WO 1997/06781